CV and Resp Control Flashcards
Functions of the CV system
Rapid convective transport of 02, glucose, FA, vitamins, drugs and h20 to tissues and rapid removal of metabolic waste from tissues
Control system - distributed hormones to tissues and secretes bio active agents eg peptides, resin etc.
Body temp regulation
Reproduction- provides hydraulic mechanism for genital erection
CO (Lmin-1)=
Heart rate(min-1)*stroke volume
Define CO in Lmin-1
Volume of blood ejected by one ventricle in one min or equal to the number of times the heart contracts in one min times the volume of blood ejected with each contraction.
SV typically 70-80 and HR 65-70 So CO is roughly 5Lmin-1
Blood pressure gradients in vessels
Aortic BP 100mmhg
Veins 0mmHg
Arterial 120/80mmHg
Darcys law
Flow= P1-P2/resistance
Poiseuilles law
Resistance = 8viscositylength/Pi*r4
Resistance in series and parallel
Series - summates ; Rtotal= all added together
Parallel- 1/Rtotal= 1-R1+1/R2 etc.
Series is a portal system eg kidney, liver, brain drawback is in reduced pressure tissue will receive less blood and vice versa with hypertension leading to damage of vessels.
If resistance halves, conductance will
Double, raising blood flow
Factors affecting local vascular resistance
Nerves especially sympathetic vasoconstrictor nerve tone
Local metabolites eg O2, CO2, H+, K+, adenosine etc
Myogenic response - stretch of vascular smooth muscle and construction
Hormones, autocoids like vasopressin, angiotensin, histamine, bradykinin, serotonin
Endothelial substances like NO, endothelin etc
Auto regulation - combo of metabolites and myogenic response
Capillary filtration coefficient
Affect the movement of water beteeen plasma and interstitial fluid
Size and number of pores in capillary wall
Number of capillaries in tissue
Expressed together with net filtration pressure to gain filtration
KfNFP= filtration (ml/min)
With starling forces—
Filtration (ml/min)= Kf((Pc-Pif)-(plasma colloid osmotic pressure-IF colloid osmotic pressure)
Auto regulation
Maintenance of a constant blood flow in face of changes in perfusion pressure
Starling forces
Intra-capillary pressure (Pc) is higher than interstitium (Pif) so fluid should be forced from plasma into If via pores
Osmotic pressure opposes this due to the plasma protein concentration called colloid osmotic pressure
Collectively called starling forces and are responsible for bulk fluid exchange
Net filtration pressure =
(Pc-Pif)-(COP-IFCOP)
Colloid osmotic pressure
Normally slightly positive value resulting in steady filtration from plasma to IF
Very small outward pressure usually and this movement is corrected by the lymphatic system
Inspiration mechanisms
Diaphragm flattens
Rib cage expands - bucket and pump handle motions (up and out)
Intrapleural pressure falls (more negative values)
Alveoli expands and alveolar pressure falls
Air drawn into lungs down pressure gradient
Expiration mechanisms
Passive at rest
Elastic recoil of lungs and chest wall follows
Negative intrapleural pressure and surfactant prevent complete deflation leaving functional residual capacity FRC
Increased ventilation expiration becomes active
Internal intercostal and abdominal muscles contract
Also recruited in sneezing and coughing etc
Intrapleural pressure becomes positive
Air actively expelled
Arterial and venous capillary pressures
Arteriole - 30mmHg
Venous - 10mmHg
NFP is positive a arterial end and negative at venous end, fluid leaves and then returns roughly 90% is returned again the rest is removed by lymphatics
Cardiac cycle
Ventricular Diastole - both atria and ventricles relaxed and ventricles full with blood, AV valves open, initial rapid filling phase then slows nearing fullness
Atrial contraction / systole pumps extra blood into ventricle
Pause in electrical activity to ensure fullness
Ventricle systole closes AV valves as ventricle pressure exceeds atrial pressure and opens aortic and pulmonary semi lunar valves blood expelled from the heart. Lasts 0.35s divided into brief isometric phase and longer ejection phase. Rapid ejection phase 0.15s 3/4 of SV ejected in the first phase. Most blood temporarily accumulates in distended elastic arteries driving max systolic pressure where cardiac arteries drain to the heart.
as the pressure decreases the backflow closes the semi lunar valves
As each chamber empties the elastic recoil and deformed myocardium cause ventricular BP to fall rapidly pushing open the AV valves terminating the isovolumetric relaxation phase and blood continues to fill the Atria in atrial diastole (starts filling in ventricular systole) and next cycle begins
Factors involved in control of breathing
Cortex- behavioural and voluntary control Hypothalamus Cerebellum Peripheral and central chemoreceptors Receptors in joints and muscles Stretch receptors Irritant receptors
All feed info into the pons in the brain to alter the diaphragm actions in the abdomen
Respiratory control
Controlled by spatially distributed ponto-medullary resp. network that generates rhythmic patterns of alternating inspiration and expiratory activities to drive and coordinate activity of spinal and cranial motoneurones
Role of the pons is not fully established
Pontine regions interact with multiple medullary compartments and modulate medullary respiratory activity and control respiratory phase transitions
The medulla and respiration
Cells in he Medulla have respiratory related activity found throughout in a number of nuclei:
Four main nuclei:
Dorsal respiratory group DRG within the nucleus tractus solitarius NTS
Ventral resp group VRG containing the nucleus ambiguus NA and nucleus retroambigualis NRA
pre-Botzinger PBC and Botzinger complex BC located near nucleus retrofacialis RTN
Pre-Botzinger complex thought to be key centre of respiratory rhythms genesis
What is thought to be key centre of respiratory rhythms genesis
Pre-Botzinger complex thought to be key centre of respiratory rhythms genesis
DRG
Contains only inspiration neurones that fire immediately prior to and during inspiration
- ramp crescendo like activity increasing steadily and ceasing abruptly
- neural activity relayed to phrenic nerves
- rate of increase and termination point controlled
- determines depth and rate if breathing
Received input from chemoreceptors and lung mechanoreceptors (IX and X cranial nerves) and higher brain centres
- stretch receptors important for determining IE phase transition and switching off activity
- within NTS nucleus tractus solitarius is an efferent/ afferent relay station
- also interacts with pontine respiratory group for control of ramp and termination point
DRG inhibitory neurones inhibit expiratory neurones in VRG and PRG
Wiggers diagram
Summarises cardiac cycle events in pressure and volume in one graph
May also include ECG and phonocardiogram
Define end diastolic volume
Volume of blood in ventricle at the end of filling period
Ejection fraction
SV/EDV
End diastolic volume
Stroke volume and ESV definition
Sv- volume of blood ejected during ejection phase
ESV- what remains at end of systole period
Ventricular myocytes
Long and narrow 60-140um length 20um diameter
Volume 15000-45000 um3
Lots of t tubules
Prominent end to end intercalated discs for transmission
Mitochondria, sarcomeres very abundant, rectangular branching bundles with little interstitial collagen.
Atrial myocytes
Elliptical shape, 20um length 5-6 diameter, 500um3, rare/no t tubules, side to side and end to end intercalated discs for transmission, contain bundles of atrial tissue separated by wide areas of collagen
Desmosomes transmit…. while gap junctions transmit…
Force
Ions/action potentials
Cardiac muscle is arranged in
Electrically continuous sheets - syncitium
Cardiac cells electrical activity
Starts with cardiac potential generated by ionic gradients and sequential ion channel activation
Resting potential -80mV from K+ moving from intercellular out of the myocytes via K+ channels so inside cell is slightly negative
Voltage gated Na channels admit brief influx of positive ions into cell at the start of an AP and depolarise the cell (phase 0)
Membrane begins to repolarise (phase 1)
Activation of long opening Ca2+ channels allows influx of calcium nearly counterbalancing K current generating a long plateau around 0 potential lasting 200-400ms (phase2) called excitation contraction coupling.
The plateau is terminated by efflux of K ions which re polarises the cell (phase3)
Resting potential (phase4)
Cardiomyocyte contraction mechanisms
Excitation contraction coupling and theCa2+ cycle
Ca cycle:
Release of intracellular Ca during systole following membrane depolarisation down t tubule and Ca channel activation. Ca released from sarcoplasmic reticulum via activated ryanodine receptors.
Increased cytoplasmic Ca binds to tropinin C and actin myosin cross bridge formation contraction cycle begins.
Relaxation- ryanodine receptor closes and Ca pumped back into SR via SERCA2a/PLB channel complex or expelled from cardiomyocyte by Ca channels. Deactivates contraction actin myosin cycle.
Fight of flight response in cardiac contraction
Rapid enhancement of cardiac contractility caused by sudden exercise or stress
Catecholamines like adrenaline or noradrenaline released in blood activating chain involving increased phosphorylation of RyR2 ryanodine receptor by protein kinase A releasing Ca into cytoplasm and increasing cardiomyocyte contraction.
What regulates the duration and contractile force of cardiac muscle
Changes in the permeability to calcium and potassium
Adrenaline increases Ca release so increases contractile force (positive inotrope)
Increases K permeability results in a negative inotropic effect reducing contractile force.
Conduction pathway overview and timing
Stimulus initiated in SAN Diffuses into atria 1m/sec AVN conduction 0.05m/sec Dispersion via bundle of His and purkinji fibres 4m/sec Endocardium to epicardium 0.3m/sec
Cardiomyocyte activation threshold value
-70 to -60
Define absolute and relative refractory periods
Absolute- period of time where a new action potential cannot be initiated
Relative- period of time when new action potential of limited magnitude can be initiated or greater stimulation is needed to generate an action potential
Factors affecting stroke volume
Filling pressure (preload) - only as much as venous return
Arterial pressure opposing ejection (afterload)
Contractility from sympathetic nerves and circulating agents
Energy of contraction
Total peripheral resistance
Ventricular preload and afterload equation
Preload (diastolic wall stress) depends on the end diastolic pressure, chamber radius and walk thickness, Laplace’s law. The afterload (systolic wall stress) depends on arterial pressure, chamber radius and walk thickness, Laplace’s law.
Length tension relation in contraction
Stretching sarcomeres increases contractile energy and an raise contractile force without increasing Ca. Stretch reduces filament overlap and increases Ca sensitivity
Frank-starling relationship and mechanism
The greater the stretch of the ventricle in diastole the greater the stroke work achieved in systole
The right atrial pressure determines preload filling pressure
The energy of contraction is proportional to the initial fibre length
Mechanism: balances output of right and left ventricles,
mediates postural hypotension- fall in CO and BP with standing
Mediates hypovolaemic hypotension following haemorrhage or dehydration
Fall in SV during forced expiration
Increased SV in exercise
Describe contractility (intropy)
The forcefullness of myocardial contraction when other effectors like stretch and HR are held constant
Can be changed by autonomic nervous system and specific drugs (inotropes)
Due to increased cytosolic Ca
There is disagreement as to whether an increase in Ca sensitivity is inotropy.
When contractility is depressed it can result in heart failure
Methods of controlling stroke volume
Frank starling mechanism increasing force/Ca relationship
Inotropes increasing cystolic Ca
Duration of cardiac cycle - only important at very high heart rates that affect ventricular filling time
Force frequency- faster heart rates produce more forceful contractions
Bainbridge reflex- veno-atrial stretch leads to increased contractility
Effect of filling time on SV
As HR increases the time for filling is reduced
This has little impact with moderate HR increase
Cardiac output is maintained as any reduction in SV is compensated for by increase in rate
As filling time is reduced the contribution made by atrial systole becomes of greater importance
The force frequency (bowditch staircase effect)
As HR increases so does contractile force
Effect is hypothetically due to an accumulation of Ca in the cytosol with increasing stimulation rate
The brain bridge reflex
Stretch receptors in both atria feedback to the ANS to regulate heart rate indirectly
Prevents blood building up in the great veins and pulmonary circulation
Further assisted by the stretching of the SAN
Effect of stretching SAN on stroke volume
Mechanical stretching of SAN increases heart rate up to 15%
Afterload
Equivalent to MABP
Acutely an increase in afterload reduces SV however long term reduced Sv leads to blood accumulation, increased CVP and activation of the frank starling mechanism
Prolonged left ventricle dilation causes further increases in contractility (anrep effect)
Increased MAP activates the baroreflex depressing cardiac function
Long term effect of increased afterload arises from all these influences
What determines blood pressure
Blood volume
Cardiac output - Darcys law P=F(CO)*R
Peripheral resistance
Venous capacitance - reduction in VC frees up venous blood increasing filling pressure and boosting cardiac output via the frank starling mechanism
Gravity- hydrostatic pressure
Arteriolar constriction from increased CO increases MAP also thus increasing PVR
The baroreflex
Pressure sensors in the carotid sinuses and aortic arch respond rapidly to acute changes in pressure by modulating the ANS via the nucleus solitarius
Adjusts CO and peripheral vascular tone to stabilise arterial blood pressure
Provides acute control of arterial pressure
The carotid sinus is stimulated by the carotid sinus nerve branching from the glossopharyngeal IX cranial nerve and the aortic nerve supplies the aortic arch branching from the vagus X cranial nerve
Increased AP firing decreases SNS and increases PNS to lower HR, LV contractility and vasodilation and increase venous capacitance. Decreases CO and peripheral resistance to correct AP.
Decreased AP does the opposite.
Gravity and hydrostatic pressure on blood pressure
The effect of gravity means blood pressure in the feet should be approx. 90mmHg greater than at the heart - hydrostatic pressure
The full effect is not normally exerted because of the venous valves
Contraction of the leg muscles expels blood from the microvascular combined with the valves - system is called the muscle pump
Because of this hydrostatic pressure only increases venous pressure by roughly 20mmHg in a walking adult
Long term blood pressure homeostasis depends on
Rental regulation of ECF by two methods:
Circulating levels of excretion related hormones eg ADH, angiotensin-II, aldosterone and ANP is controlled by CV receptors - the renin angiotensin system
Or by pressure natriuretsis causes and increase in salt and water excretion when renal artery pressure rises
Chronic intake of water and salt and the left to right shift of the renal function curve affect long term ABP
Define pressure diuresis and natiuresis
Increasing arterial pressure causes a corresponding rise in renal urinary output (diuresis) as well as sodium output (natiuresis)
Renin-angiotensin system
Renin (enzyme) produced from prorenin and released by kidneys is first step in the RAS cascade
Combines with angiotensinogen from the liver to form angiotensin I which is converted to ang II in pulmonary circulation by ACE enzyme. This causes a right to left shift in the renal function curve meaning ang II causes water and salt retention increase plasma volume and blood pressure.
Aldosterone secreted by adrenal glands acts on the kidney to increase Na reabsorption, stimulates thirst centres and causes increased ADH release from pituitary. ADH stimulates water retention also.
VRG
Contains both inspiratory and expiratory neurones
- active during respective phase of breathing
- rostral nucleus retroambigualis (rNRA) contains inspiratory neurones
- caudal NRA contains expiratory neurones
- nucleus ambiguous including premotor inspiratory neurones to external intercostal and accessory inspiratory muscles and motor neurones to the laryngeal muscles
VRG neurones mostly inactive during quiet breathing - just repetitive inspiratory activity from DRG and passive elastic recoil from chest wall/lung.
VRG expiratory neurones activate expiratory muscles when ventilation increases and expiratory becomes active. Activated by the spillover of DRG activity.
Reciprocal activity with DRG - VRG expiratory neurones also inhibit DRG inspiratory neurones during expiration acting as inspiratory switch off.
Respiratory rhythmigenesis
Pre-Botzinger complex thought to be the key centre of respiratory rhythmogenesis
- contains neurones with intrinsic pace making capabilities
- demonstrate cyclical firing without additional synaptic input.
Contains both expiratory neurones, vagal and glossopharyngeal motor neurones.
Input from the lung and peripheral chemoreceptors to the complex via the NTS
botzinger and pre-botzinger complexes provide input to the DRG and VRG
Pontine respiratory group
Role of PRG in generation and control of respiratory rhythm is not fully established
PRG compromised of medial parabrachial nucleus - expiratory neurones.
Lateral parabrachial nucleus and Kolliner-Fuse nucleus - inspiratory neurones.
Reciprocal connections with the medulla
Involved with phase switching - inspiration to expiration and control of respiratory rate
- secondary mechanism to lung stretch receptor feedback
- increased PRG activity shortens medullary inspiratory neuronal activity and switches to expiration earlier
- Respiratory rate increased
- lesions/absence result in increased tidal volume and decreased rate
PRG connections to medullary circuits appear critical for coordinating activity of expiratory and upper airway muscles during expiration.
Has involvement in control of foetal breathing movements.
Respiratory input from other brain centres
Cerebral cortex - descending influencers allow voluntary control of breathing
- neurones bypass ponto-medullary centres and synapse directly with spinal respiratory motor neurones
- proof from congenital central hypoventilation syndrome CCHS where autonomy control is lost by cortical control remains the same, so they have adequate ventilation while awake but loose this during sleep
Hypothalamus - temperature, pain and emotion influence breathing
Cerebellum - centre of sensorimotor coordination, coordinated equilibrium, posture, muscle tone, has considerable input from sensory systems but operates as part of motor systems. Has deep cerebellar nuclei involved in respiratory control. Fastigial nucleus involved in response to CO2 and O2 - activation increases ventilation and is also a chemosensitive site.
Dentate nucleus involved in maintaining muscle tone in upper airway. Role of cerebellum in SIDS in posture
Respiratory control by O2 and CO2
Ventilation is sufficient to ensure Hb is close to 100% saturation to support O2 demand
CO2 closely regulated as variations in this directly affect pH, small variations in which can alter physiological function widely.
PaO2 not as closely regulated PaCO2. Adequate Hb saturation is achieved over a wide range of PaO2 levels
Complex mechanisms maintain gas homeostasis - chemoreceptors central and peripheral.
Central chemoreceptors
Located on the ventrolateral surface of medulla, the pre-Botzinger complex, retrotrapezoid nucleus in Pons, parafacial respiratory group in medulla, raphe nuclei in brainstem reticular formation, locus ceruleus in Pons, nucleus tractus solitarius in medulla, fastigial nucleus in cerebellum.
They respond to changes in PaCO2 (account for 70% response to CO2) and pH but not O2 due to blood brain barrier permeability to CO2 but not HCO3- or H+
Affected by changes in arterial PCO2 not arterial pH
Respond to pH of CSF via PCO2 changes
Increase in PCO2 causes near linear increase in ventilation rate
Provides main drive for ventilation normally
Comparatively slow to respond as needs changes in CSF to occur
Peripheral chemoreceptors
Main oxygen sensors
Located in bifurcation of common carotid arteries (stimulated by IXth cranial/glossopharyngeal nerve) and aortic arch (stimulated by achy cranial/vagus nerve)
Fast response due to large blood flow being highly vascularised
Detect PaO2, PaCO2 and pH
Decrease in O2 or pH or increase in CO2 causes increased ventilation
10-40% of total hypercapnic response
Respiratory response to CO2 mediated by
Both central and peripheral chemoreceptors
Peripheral respiratory response mediated mostly by
Carotid chemoreceptors as aortic arch is mostly baroreceptors
Airway and lung sensory receptors and response
Nasal - sneeze and diving reflex
Epipharyngeal - aspiration reflex
Pharyngeal - swallowing
Laryngeal - cough and apnea
Slowly adapting receptors in trachea/bronchi - hering-Breuer inflation and deflation reflex, bronchodilation and tachycardia
Rapidly adapting receptors in trachea/bronchi - hering-Breuer deflation, cough, bronchocinstriction, mucus secretion
C-fibre endings - pulmonary chemoreflex, rapid shallow breathing, bronchocinstriction, mucus secretion, bradycardia, hypotension.
Reflex control of ventilation
Upper airway:
Irritant receptors provide protective reflexes to dust etc. And expiratory reflexes like coughing, apnea and laryngeal narrowing
Pulmonary stretch receptor reflexes:
Hering-Breuer inflation reflex prevents lung over inflation for protection
SAR stimulated by lung inflation results in cessation of inspiratory activity but this has little importance on breathing at rest
Hering-Breuer deflation reflex:
Helps maintain FRC and prevent actelectasis
RAR stimulated by deflation below FRC provoking strong inspiration, commonly seen in neonates.
Heads paradoxical reflex:
RAR stimulation by lung inflation produces augmented inspiration eg in first breath in perinatal period only or sighing in adults
Where do respiratory reflexes arise from
Pulmonary vascular receptors
Juxta-capillary receptors/pulmonary C-fibre receptors - activated by physical engorgement of pulmonary capillaries or increased pulmonary interstitial volume, stimulation results in rapid shallow breathing, bronchoconstriction and mucus secretion. Unsure of relevance at rest.
Airway mucosa C-fibres cause coughing
Exercise and ventilation
Very unsure of mechanisms likely multiple involved
Respiratory regulation by feedback control?
PaO2, CO2 and pH remains relatively unchanged by moderate exercise so what drives these compensatory changes?
Feedforward control by central command - parallel stimulation of resp centre by limb movement motor commands - motor cortex and hypothalamus
Feedback from group III-IV limb afferents experiments show this.
iii For movement, local touch, pressure and tendon or muscle stretch
IV for mechanical distortion, chemical (H+,La, K+), thermal stimuli
Feedback proved important by intrathecal injection blunting response.
PECO experiments discount presence of meta bore rotor in muscle.
Other mechanisms include K+ release by exercising muscles stimulates peripheral chemoreceptors - sinusoidal changes in work rate indicated disproportional relationship between K+ and VE during moderate exercise
Oscillations - rate of breath oscillations in PaCO2 resulting from phasic fluctuations in PACO2 matching those of carotid chemoreceptors firing. However bilateral carotid body resection has no effect on magnitude of exercise hyperpnoea
Vestibular feedback - head movement sensed at onset increasing ventilation
Behavioural response- phase 1 a learned response from repeated exercise
Cardio dynamic theory
Ventilation and pulmonary flow must increase in tandem as there is no hyperventilation and a fall in PaCO2 at the onset of exercise
Hyperpnoea is mechanically mediated via cardiac afferents in response to the right ventricular strain
Heart transplantation sir artificial hearts had no effect on exercise hyperpnoea
Neuro-humoral control of ventilation
Phase 1 if exercise is neurally mediated by feedforward control (motor command) and feedback (movement)
Phase 2 and 3 controlled by neural mechanisms muscle and vascular augmented by humoral PCO2 feedback from chemoreceptors
A feedforward feedback mechanism that maintains such a close regulation of PaCO2 makes detecting an error signal very very difficult in experiments
Cellular components of the heart
Contractile cells - cardiomyocyte
Vasculature
Stem cells
Extra cellular matrix
Cardiac homeostasis overview
Myocardial mass - non replicating terminally differentiated myocytes Ageing myocytes p16POS dying myocytes Stem cells and progenitors Cycling immature myocytes Back to myocardial mass
Used to believe the heart was post mitotic and any change in heart mass was due to cell growth alone not replication
Physiological cardiac growth experiment results
Rats-
Exercise training improved max exercise capacity (VO2max)
Walk thickness increased
Increased end diastolic and systole diameter
Increased fractional shortening
Increased ejection fraction
Increased left ventricular mass
Increased heart weight through cardio myocytes hypertrophy
Physiological myocardial growth is through…
Hypertrophy of cardiomyocyte and cardiomyocyte hyperplasia increasing size and number
There is a drop out loss of CM that increases with age
There is ongoing cell death and regeneration throughout heart lifespan
Evidence for cardiomyocyte renewal in humans - and critique
Studied individuals born around or after nuclear bomb tests
c14 concentration of cardiomyocyte nuclei DNA corresponded to atmospheric concentrations of c14 several years after birth suggesting post natal cardiomyocyte DNA synthesis and renewal
Cardiomyocyte renew at rate of 1% per year at age of 25 and 0.45% at age of 75.
50% heart replaced over a lifetime
Critique-
Patient cohort, patient pathological and physiological status will effect turnover
How do we know cells were in isolation completely from heart no contaminating cells.
Data analysis mathematical model means assumptions were made including that cardiomyocyte renewal is 0 which is not true as this would mean no heart changes in mass ever.
Potential Source of new cardiomyocyte
Stem cells (cardiac stem cells) Division of pre-existing cardiomyocyte
Define stem cells
Unspecialised cells can give rise to many cell types
Can divide without limit to replenish themselves- clonogenic and self-renewing
Differentiate into diverse range of specialised cell types such as muscle cell, RBC, neural cell - pluripotent or multipotent
Found in embryonic tissue (blastocyst) or tissue specific stem cells
Types of adult stem cells
Haematopoietic and mesenchymal in bone marrow Satellite in skeletal muscle Neural in neuronal tissue Epithelial In digestive system Epidermal in skin Cardiac in heart Umbilical cord and amniotic in cord blood and amniotic fluid Adipocyte In fat Tendon in tendon and cartilage
Terminals of cardiac stem cells c-kitPOS
Capillary
Myocytes
Arteries
Cardiac stem cell pathway to become cardiomyocyte
Clonogenic self renewal phase
Differentiation and multipotency - expression of different cardiac genes and proteins to determine contractile cell, vascular smooth muscle or endothelial cell.
Genes involved in cardiac development
C-kit - receptor from KIT gene
Alpha sarc actin - protein
Nkx-2.5 - transcription factor specific to heart development
MEF2C - specific transcription factor to heart development
Evidence from genetic fate mapping study that stem cells refresh adult mammalian CMs after injury
Results-
Up to 1 year normal ageing no change in GFP+ CMs and stem cells don’t refresh at significant rate
After myocardial infarction or trans aortic constriction - GFP+ CMs decreases by around 15% so stem cells do replenish CMs at a significant rate
Hsieh et al. 2007
Second paper shows after ISO injury GFP+ CMs decreases around 10% so stem cells replenish CMs after ISO injury
Ellison et. Al. 2013
Third paper total of 6 nuclei out of 4190 myocytes analysed in normal adult heart which are diploid, mononucleated and GFP+. Therefore 0.14% claimed to originate from pre-existing myocytes in normal heart. Consistent with 2007 data.
11 nuclei 7063 myocytes analysed in infarcted heart which are diploid, mononucleated and GFP+ meaning 0.16% claimed to originate from pre-existing monocytes In injured heart vs 15% from stem cells. Senyo et al 2013.
Diffuse myocardial injury and cardiomyocyte renewal
C-kit+ stem cells do contribute significantly to Cm renewal after DMI
Cardiac stem cells proliferate after isopropanol ISO injury and express specific cardiac factors like NKX-2.5 etc.
Cardiomyocytes also go into division (very small numbers)
By 28 days 5% of mass has been restored (compared to the 8% lost therefore almost 100%)
After 3 days histology shows infiltration of inflammatory cells in subendocardial layer of heart followed by spontaneous regeneration
By 28 days all rats were indistinguishable from non injured rats and cardiac function is completely normal. No scarring or fibrosis etc.
Ablation of eCSCs blocks myocyte regeneration and cardiac functional recovery leading to death by heart failure - removed stem cells with chemotherapeutic drug to kill all proliferating cells
Ellison et. Al 2013
Predominant source of new cardiomyocyte
From endogenous cardiac stem cells not division of pre existing CM after injury
Heart metabolic needs
700mg ATP
6000grams per day for function
Almost entirely dependent on mitochondria oxidative phosphorylation - 35% of cardiac mass is mitochondria
Myocardial oxygen consumption can intense up to 6fold during max exercise
Oxygen extraction of heart
70-80% has very high capillary density in tissue approx 4000 capillaries per mm3
Perfusion=
Average aortic pressure/total coronary resistance (including epicardial, inner layer and whole cycle resistance pressure)
Coronary arteries and what they supply
Right CA arises from the right aortic sinus gives off branch to upper right atrium then runs down in the right atrioventricular groove supplying the right ventricle
Passes round to underside of the heart- terminal branch is the right interventricular artery
Left CA arises from the left aortic sinus behind the pulmonary trunk.
Divides quickly into the circumflex branch and several others to the left ventricle, longest of which is called the left interventricular artery or left anterior descending (LAD).
Circumflex runs to the underside of heart in left atrioventricular groove sending more branches to the LV.
All major CA divide into epicardial arteries and intramuscular arteries penetrate the myocardium perpendicularly to form subendocardial arterial plexuses.
Define coronary flow reserve
Ability of the coronary arteries to increase blood flow under stress
It’s the ratio of maximal flow to resting coronary blood flow
What is a CT coronary angiography
Computer tomography coronary angiography CTCA is a technique proved to provide high sensitivity and negative predictive value for identification of anatomically significant coronary artery disease
Why do the main coronary arteries run on the surface of the heart
To avoid being compressed during systole of the cardiac cycle and avoid excess stress or leaking of the vessel which could lessen blood perfusion
Main predictor of oxygen consumption in the heart
Heart rate - doubling heart rate doubles oxygen consumption effectively
Describe venous return of the cardiac veins
Most blood from the left ventricle drains into the coronary sinus
The anterior cardiac vein receives blood from the right ventricle
Both open into the right atrium
Thebesian veins drain a small portion of coronary blood directly into the cardiac chambers and account for true shunt
Determinants of coronary blood flow
Perfusion pressure - during systole blood vessels are compressed mostly affected in the subendocardial layers. Intramyocardial blood is propelled forward to the coronary sinus into epicardial vessels in this time. Flow resumes during diastole with relaxed muscle.
Perfusion time - increase in heart rate reduces diastole time and therefore perfusion time
Vessel wall diameter - vasomotor tone and deposits inside the vascular linen determine diameter. Various mechanisms regulate this tone usually favouring dilation.
Factors influencing vasomotor tone of heart
Myocardial metabolism - tone almost exclusively determined by local metabolic oxygen demand. Hypoxia causes coronary vasodilation directly and also releases adenosine and opens ATP- sensitive K channels. Pre-capillary sphincters relaxed and more capillaries recruited.
Autoregulation - at rest CBF remains between 60-140mmHg but beyond this flow becomes pressure dependent. Probable mechanisms include myogenic response to intraluminal pressure changes and metabolic regulation. Myocardial oxygen tension and presence of vasoconstrictors or dilators influence lumen size.
Nervous control - generally weak
Humoral control
Vascular endothelium - modulates contractile activity of underlying smooth muscle via vasoactive substances such as NO and bradykinin for relaxants or endothelin for constrictors.
Where does coronary autoregulation mostly take place
Arterioles
Purpose of coronary autoregulation
Capability of heart to self determine how much blood it draws from aortic blood.
Speed of blood in low resistance larger coronary arteries
1.5m/second
During a myocardial infarction there is … ischaemia
Transient ischaemia - across all layers of the vessel wall
Purpose of coronary autoregulation
To keep heart perfusion to match metabolic oxygen demand. Without requiring too much blood from circulation
At rest it is a linear relationship between coronary flow and perfusion however with increasing perfusion pressure flow plateaus to create a greater coronary flow reserve by favouring vasoconstriction therefore allowing more vasodilation to be possible as oxygen demand increases.
With atherosclerosis this vasodilation reserve can be used to compensate for loss of perfusion rather than autoregulation however as it worsens there is less and less coronary flow reserve available until it can no longer cope or compensate resulting in angina/heart failure
Why do people present with breathlessness with cardiac pressure problems
When oxygen is short less ATP is synthesised making the heart stiffer and diastole less effective increasing the end diastolic pressure creating extra pressure and fluid in lungs presenting clinically as breathlessness
Effect of stress on coronary flow
Can almost triple flow
Functional anatomy of coronary circulation
Epicardial coronaries (>500um) have 10% resistance, 5% of coronary blood volume
Pre arterioles (500-200um) 30% resistance, 2-3% blood volume regulated by shear stress and sympathetic control
Arterioles (200-10um) 50% resistance, 2-3% blood volume regulated by shear stress, myogenic control, metabolic control.
Capillaries (10um) receptors to pH, adenosine etc. Which quickly produce vasodilation or constriction response
Venous system shares 10% resistance with capillaries and 90% of blood volume in coronary circulation
The ischamic cascade
Reduced blood flow or increased metabolic demand not met Cellular hypoxia Abnormal relaxation Abnormal contraction Abnormal repolarisation - ECG Angina Infarction arrhythmia and heart failure
Angina treatment
Statins to reduce cholesterol and evidence suggests can reduce plaque size
Structure of blood vessels
Endothelium innermost layer
Internal elastic lamina and fibrecollageninous tissue make up the tunica intima
Smooth muscle makes up tunica media
Fibrocollaginous tissue, external elastic lamina and another F.C. tissue layer makes up the tunica adventitia
NO as a vasodilator
Synthesised from L-arginine and oxygen released by endothelial cells accounts for relaxation of strips of vascular tissue and inhibition of platelet aggregation and adhesion attributed to the endothelium derived relaxing factor.
Nitric oxide synthase isoforms
Enzymes convert L-arginine with oxygen to NO.
eNOS- endothelial constitutive isoform is calcium calmodulin dependent
iNOS- inducible isoform with high NO output released from smooth muscles and macrophages is calcium independent
nNOS- neuronal constitutive isoform is calcium dependent
All bind calmodulin and contain haem.
Generation and activity of endothelial nitric oxide
Ca2+ enters cell and NO synthase converts L-arginine to NO and citrulline
NO travels to smooth muscle and binds guanylyl Cyclase converting guanosine triphosphate to cyclic GMP and protein kinase which causes a cascade to relax smooth muscle.
Uncoupling NO synthesis
BH4 is an essential cofactor for NOS activity
Reduced BH4 or L-arginine uncouples NO synthesis from NADPH consumption to generate superoxide OONO- (oohnooo)
Reduced NO and increased oxidative stress impair vascular reactivity further
Calcium and phosphorylation dependent activation of eNOS
ENOS bound to cav with Ca bonding gives eNOS and Calmodulin which binds to hsp90
Phosphorylated removing CaM leaving two phosphates in place with Akt at residues Thr495 And Ser1177
Calcium binds and removes one phosphate resulting in NO production?
Other endothelium derived vasodilators besides NO
Endothelial hyperpolarising factor - factor which reduces intracellular Ca in smooth muscle cells (k+, cytochrome P450 metabolite, gap junctions)
Prostacyclin PGI2 - generated in arachodonic acid by cycloxoygenase. Activates cAMP pathway in smooth muscle cells to reduce intracellular Ca2+ and myosin light chain kinase activity
Endothelium derived vasoconstrictor
Endothelin - binds ET receptors in smooth muscle cells to increase intracellular Ca and smooth muscle cell contraction
Describe overall control of blood flow
At rest blood vessels are under sympathetic constrictor tone
Arteriole and venous tone regulated at local and central levels
Local control allows matching between tissue metabolic needs and blood flow
Physical factors, local metabolites, local mediators, Nerves and hormones control tone
Growth of new blood vessels used to regulate tissue blood supply
Autoregulation
Vascular resistance not constant with pressure
Also changes with local metabolic rate and oxygen delivery
Acute regulation requires rapid change in resistance of blood vessels locally
Long term regulation involves remodelling of existing vessels or formation of new vessels - angiogenesis
Acute autoregulation
Maintains tissue perfusion
Changes in arteriolar diameter take 30-60 seconds to develop fully
Only operates sober limited range of pressures
Important in renal, coronary and cerebral circulations to regulate capillary pressure and prevent oedema
Mechanisms-
Myogenic
Vasodilator removal
Tissue fluid pressure
Describe myogenic mechanism of autoregulation
Involved in acute AR
Increased pressure increases arteriolar wall tension
Vascular smooth muscle contracts when stretched and relaxed when passively shortened
Action is purely myogenic no mediators needed
Involved activation of stretch sensitive L type Ca channels on cell membrane and protein kinase C to enhance contractility
‘Braking’ mechanisms-
Ca activated K channels which hyperpolarise smooth muscle cell to attenuate depolarisation
Shear induced endothelial NO release
Describe tissue pressure and autoregulation
Involved in acute AR
Increased perfusion pressure increases bulk outflow of capillaries
Locally increased tissue volume increases tissue pressure
Elevated tissue pressure reduces transmural pressure distending micro vessels
Reduced vessel diameter increases resistance
Mainly increases capillary and venue resistance
Describe vasodilator wash out and acute autoregulation
Increased blood flow removed vasodilators and local metabolites this lowering interstitial concentration to increase vessel tone
Hyperaemia
An excess of blood in vessels supplying an organ or other part of the body!
Active/metabolic type- important in active tissues like skeletal muscle, heart and brain
Increased tissue activity causing local vasodilation
Fall in vessel resistance occurs due to local release of metabolites
Eg adenosine, K ions, acidosis, local hypoxia, phosphate ions, hyperosmolarity or CO2
Reactive/ischaemic type- if blood flow to tissue is transiently stopped or slowed significantly vasodilation occurs after flow is restored
Myogenic response and local accumulation of vasodilators facilitate
Reperfusion injury occurs after long periods of ischaemia
Autacoid mediators
Physiologically active substances produced by the body active for localised brief periods of time
Histamine- from mast cells and leukocytes in response to injury, vasodilator produces extravasation of plasma proteins. Responsible for local oedema and inflammation. Increases NO release from endothelium via histamine receptors
Bradykinin- vasodilator formed by enzyme kallikrein during inflammation, contributes to hyperaemia by increasing NO release from endothelium. Pain producing
Serotonin- derivative of tryptophan, released from platelets to cause vasoconstriction of arteries and veins
Thromboxane- formed from aracidonic acid and released from platelets to cause vasoconstriction. Synthesis inhibited by aspirin.
Neuronal and hormonal control of blood vessels
Parasympathetic and cholinergic sympathetic dilatory fibres
Sympathetic vasoconstrictor fibres
Cholinergic receptors for vasodilation
Beta receptors for vasodilation
Alpha receptors for constriction in response to blood catecholamines
Neural control of vessel tone
Most vascular beads are under sympathetic constrictor tone
Stimulation of alpha receptors by noradrenaline or adrenaline produces vasoconstriction
Skeletal muscle also has beta receptors that vasodilate when stimulated
Some tissues (skin and skeletal muscle) have sympathetic cholinergic nerves that produce vasodilation
Very few tissues have parasympathetic nerves to blood vessels (some glands and erectile tissue)
New prevention of CV disease
Random clinical trials - intervention trials compare clinical end point
But are costly and time consuming
Surrogate markers can be used in place of hard clinical endpoint to allow measurement of factors to indicate and prevent CV disease in patients
Surrogate endpoint definition
A bio marker intended to substitutes for clinical endpoints
Expected to predict clinical benefit based on epidemiological, therapeutic, pathophysiological or other scientific evidence
Surrogate measures of outcome for CV disease
Parallel - able to predict without being involved in cause or pathway
Direct - more common, surrogate can have direct causal role in disease outcome therefore can be used to predict outcome. More robust measures
Essential criteria of surrogate measures
Linkage- must relate to clinical endpoint parallel or directly and be established by epidemiology and clinical studies
Efficiency- must be easy to measure, availability, with change preceding outcome eg before disease occurs
Congruency- anticipated benefits or harm in outcome measures
Examples of CVD surrogates
Blood pressure - closely related to CV events
Estimated a decrease in 5mmHg there is a decreased risk of stroke by 14% and CHD by 9%
Lipids - LDL cholesterol
Closely related to Coronary artery disease
Large number of clinical trials supporting reducing LDL reducing CAD related endpoints
Vascular function and structure newly investigated surrogates
Novel CVD surrogates
Flow mediated dilation
Intima-media thickness and plaque
Pulse wave velocity - aortic stiffness
Critical role of endothelium in atherosclerosis
Endothelium derived mediators eg NO Inhibit adhesion molecules Are anti inflammatory Antithrombotic Anti proliferative of smooth muscle Regulate vascular tone - assessing this function is most practical way of measuring endothelial function
Endothelium function in CAD
Study assessing coronary endothelial function predicts CV disease
147 patients administered acetylcholine into coronary blood vessels and assessed dilation response
In healthy arteries causes vasodilation
With endothelial damage the response in blunted or leads to vasoconstriction
Patients experiencing CV events during follow up had significantly increased vasoconstrictor responses to Ach infusion meaning increased risk of CAD.
Good link to CV events however need non invasive technique and need to assess congruency and efficiency
More recent techniques including Doppler echocardiography, position emission tomography and magnetic resonance imaging for assessment can be non invasive measurements of coronary vasculature YAY,
Best validated technique to date is ultrasound of brachial artery reactivity (Cohn et al.,2004)
Vasodilation by endothelium derived NO
Synthesised from L arginine by eNOS reducing NADPH to NADP in endothelium then NO released and acts on smooth muscle causing relaxation by activating soluble guanylyl cyclase which converts GTP to cGMP activating cGMP protein kinases causes relaxation
Flow mediated dilation and endothelial function as a CVD surrogate
NO relaxation pathway
Increasing blood flow increases NOS release and so NO release and smooth muscle relaxation increasing artery diameter
Assessed by ultrasound usually in upper arm in brachial artery
Non invasive
Blood pressure cuff used to stop blood flow and release to increase flow
Measure baseline for 1 min diameter recorded
Cuff inflated for 5 mins
Post hyperaemia recorded for 2-5min with blood flow released again
Reduced diameter indicates reduced endothelial function
Infusion of L-NMMA (NOS blocker) prevents the dilatory response of vessels indicating this is hugely controlled by NO release
Technique needs experienced sonographer, operator dependent and sensitive to arm position. Needs very strict protocols to standardise procedure.
Many studies show FMD is closely related to risk factors for CVD so may be useful surrogate
A higher FMD is associated with a lower event rate of CVD
Some improvement in FMD shown with statin and anti hypertensive therapy but not conclusive - antioxidants inconclusive mostly no improvement in large studies
Carotid intima media thickness and CVD surrogate measures
2d ultrasonography measure distance between intima and media for IMT using edge detection software very accurate
Any thickness in IMT suggested to result from plaque development
Can measure very early or advanced stages of plaques
Carotid artery used as bifurcation is prone to atherosclerosis
Non invasive
Some training needed and mostly operator dependent
Very reproducible results
Increased carotid IMT is associated with risk factors of CVD so can indicate nicely
Strong predictor of CVD bEtter predictor of MI and CAD
reduction in IMT improves clinical outcome with statin therapy
ACAPS trial 40-79 year olds with elevated LDL-c lovastatin therapy had regression in IMT. Indirect evidence.
Physiology of large arteries
Visco-elastic arteries increase diameter with left ventricle contraction or increase in pressure
Elastin very high concentration
Can increase stiffness with gradual pressure increase constantly
With age there is a reduction in compliance and diameter increase is less further increasing intra-aortic pressure
Consequence is eventually the artery can no longer propel blood increasing chance of clotting
Measure of arterial stiffness and pulse wave velocity as CVD surrogate
Distensibility = difference in volume/difference in pressure * volume
In practice is measured as max-min diameter/pulse pressure*diameter
Pulse wave velocity - in stiff arteries pressure increase is greater and speed of blood while is less in an elastic one.
Inverse association between PWV and change in volume and pressure.
Carotid and femoral pressures measured and PWV calculated.
PWV= distance/transit time
A High value indicates stiff aorta
Non invasive
Some training needed mostly operator dependent and reproducible results
PWV increases with age and blood pressure but has little association with other factors for CVD. However is a novel surrogate factor as a high PWV shows increase in likelihood of CVD later on
No current therapies targeting aortic stiffness so Unknown if able to improve outcome but reducing blood pressure reduces PWV so could potentially have beneficial effect.
IMT and aortic stiffness relations
No correlation between either factors due to having very different pathologies in wall of blood vessel so although often concurrently occur do not have an effect on one another and often also occur independently of one another
Describe sarcomeres
Two Z lines, myomesin in the centre two c proteins either side and distance between is the M line
Actin extends from z lines inwards overlapping with myosin thick fibres
Length of myosin is the A band
Length between ends of actin molecules is the H band
Length between myosin of different sarcomeres is the I band
Tropomyosin and troponin bound to actin
Nebulin extends from z band along length of the actin filament. Acts as a template for regulation of filament length
Titin extends from z disc to the M line closely associated segment with myosin and maintains central positioning in sarcomere. During relaxation also generates passive tension through elastic extension when sarcomere is stretched
In cross section what pattern does striated muscle show
Regular lattice
Compare and contrast skeletal and cardiac muscle
Very similar
Myofilaments bound by sarcolemma which dives down at every z line forming blind ended invaginations called transverse (t) tubules
T tubules are absent in atrial, neonatal and avian heart cells.
Just under t tubules membrane is terminal cisternae of intracellular SR
Intimate association between SR And Ttubules essential for excitation contraction coupling
T tubules In cardiac muscle are larger and fatter than skeletal
Cardiac muscle has more mitochondria as cannot anaerobically respire and cannot be allowed to fatigue while skeletal muscle can
Only significant difference is fine structure of junctional SR
In skeletal muscle the SR t tubules SR interface forms a triad structure
In cardiac cells the terminal cisternae are more discrete and tend to appear as double structure with t tubules called dyads
Ventricular myocyte shape and join
Brick like to fit together and form a syncytium - single cell or cytoplasmic mass containing several nuclei formed by fusion of cells or nuclei division. Ends of cells form intercalated discs
Ionic basis of membrane potential
High K inside cell at rest giving negative cell potential -90mV
During action potential Na and Ca permeability increases and channels open depolarising cell as ions enter cell
Repolarisation caused by delayed increase in K permeability and K+ ions leave the cell
Too many leave initially causing hyperpolarisation followed by stable resting again
Action potential time of skeletal and cardiac muscle
Skeletal - 1ms
Cardiac - 200-400ms long depending on heart rate and species
Cardiac much slower to prevent tetany and protect against re-entrant arrhythmias whereas this is not the case in skeletal muscle so they favour faster summated contractions
Ion translocations proteins
Ion channels - ions move down their electrochemical gradient
Ion pumps - ions driven across membrane using metabolic energy usually ATP usually against their concentration gradient
Ion exchangers/symports - ions driven by another ions ionic gradient often exploiting the Na gradient eg glucose/Na transport
Calcium influx in muscle contraction
Extracellular Ca is essential to initiate cardiac ventricular myocyte contraction however is not needed in skeletal muscle initiation
Intracellular Ca and cardiac excitation
Action potential triggers an intracellular transient of Ca
Cardiac electrical activation is closely followed by a rise in intracellular Ca
Resting Ca is roughly 100nM and rises to peak of 1uM in about 30ms before falling back to resting and this activates contraction after slight delay.
Excitation and release of Ca - voltage induced Ca release and calcium induced Ca release
voltage induced - Action potential travels down t tubule and voltage gated L type Ca channels open
Ca induced - Ca influx activates RyR receptors and causing Ca release
Ca channels positioned just under Ca channels of t tubule (T tubule contains clusters of L type Ca channels aka dihydropyridine DHP receptors)
DHP receptors are voltage gated so open when depolarised the mouth of these is very close to the SR Ca release channels (ryanodine receptors)
These are very huge - can be seen by electron microscope sticking out of SR
Rest of SR membrane covered in Ca ATPase pumps to pump Ca back into stores after excitation. (SERCA pumps) surrounded by accessory protein called phospholamban PLB
Contraction cross bridge cycle
Attachment- myosin head tightly bound to actin molecule of thin filament (rigor state)
Release- ATP binds to myosin head indices release of actin and muscle relaxes - without ATP can stay in state of rigor
Bending- ATP causes myosin head to bend and initiates breakdown of ATP to ADP and inorganic phosphate which remain there
Myosin head binds to new actin site and iP is released
Release increases binding affinity
Myosin generates force to straighten and in doing so performs power stroke moving 5nm shortening the sarcomere
ADP lost during this stage
Release of ADP results in reattachment of myosin head to actin filament and rigor state reestablished
Myofilament Ca and tension relationship
Sigmoidal curve
Ca sensitivity and max activated force of contraction can be altered by drugs and other factors
Temperature
PH - acidosis decreases force
Inorganic phosphate - increased Pi decreases force
Drugs
Length tension sarcomere relationship
Increasing sarcomere length initially facilitates overlap between actin and myosin hence increases force produced by increasing cross bridge formation
In cardiac muscle is about 2.25um before this stretch becomes too great pulling the sarcomeres apart and losing cross bridge formations causing force to decline again
In cardiac muscle this accounts for 20% increase in force but rest is determined by length dependence of Ca sensitivity while skeletal muscle is mostly determined by this model
Length dependence of Ca sensitivity
Increasing sarcomere length increases Ca sensitivity and maximally activated force
Effect is mediated by sensitivity of troponin C for Ca
Increase in max activated force is mediated by effects of myofilament overlap from length tension relationship.
Force frequency relationship
Increasing the rate of cardiac contraction results in increased tension development
The staircase effect/treppe effect
When the frequency of heart rate increases so does the SR Ca content and the force of contraction
Force frequency relationship and failing hearts
In failing hearts the force frequency becomes negative and force decreases with increasing frequency
Due to down regulation of SERCA and up regulation of Na/Ca exchange and elevation of Na intracellularly
These combine to result in more Ca extrusion between beats and less Ca cycling through SR
Key feature of why many failing hearts don’t respond properly to exercise or beta receptor stimulation
Define heart failure
Inability to provide adequate CO to support needs of tissues or can do so but only at the expense of increased filling pressure
Types- cardiogenic shock (acute heart failure) or chronic heart failure
Pressures in heart
Systemic veins 5mmHg
Pulmonary artery 30mmHg
Aortic pressure kept constant by baroreceptors at about 100mmHg
Right heart failure
Impaired pumping causes output of both ventricles to reduce so CO falls
Fall in right side causes fall in left
Systemic venous pressure rises to 10mmHg because right ventricular end diastolic pressure increases
Circulatory reflexes tend to maintain mean pulmonary artery pressure, Left ventricular end diastolic pressure and aortic pressure and relatively normal levels
3 primary causes of heart failure
Pressure overload - hypertension, aortic stenosis
Volume overload - aortic or mitral valve regurgitation
Contractile dysfunction - ischaemic heart disease, myocardial disease, pregnancy, congenital cardiomyopathies
Left heart failure
Impaired pumping causes output of both ventricles to reduced and CO falls
Pulmonary venous pressure rises eg to 18mmHg because left ventricular end diastolic pressure increases and backs up
Circulatory reflexes tend to maintain mean aortic pressure at virtually normal levels
Elevated pulmonary venous pressure is transmitted through lungs because they’re low resistance causing slight rise in pulmonary artery pressure eg to 40mmHg
Congestive heart failure
Principally due to left heart failure in turn affecting the right ventricle
When moderately severe is accompanied by fall in CO
Significant elevation of pulmonary venous pressure eg 16mmHg because LEDP increases
Modest elevation of MPAP eg to 40 MmHg and systemic veins eg 8mmHg backs up
Reflexes tend to keep MABP virtually normal
